To accurately compute free energies of complex biomolecular systems there are two key prerequisites: the accurate description of inter- and intramolecular interactions, and adequate sampling of all relevant conformational degrees of freedom. Include the possibility that conformational dynamics may be coupled to complex electronic processes or chemical reactions, where quantum mechanical (QM) methods are needed, and this task becomes extremely daunt- ing. Currently, whenever accurate computations of biomolecular systems are essential, the tool of choice is hybrid quantum mechanical / molecular mechanical (QM/MM) calculations, however, the application of these techniques to free energy simulations (FES) is far from common. Herein, we aim to develop a set of robust, ef?cient, and accurate new techniques that will make the application of QM/MM FES nearly routine. These methods will be subsequently ap- plied to study two classes of biomolecular applications that present extreme challenges to current techniques. Namely, the accurate computation of (1) absolute pKa as a function of ligand binding and reaction (e.g., accounting for tran- sient interactions), and (2) free energy differences of binding as a function of tautomerism. The scienti?c results will be closely tied to activities aimed at improving access to these advanced techniques.